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Novel small molecules targeting the KChIP-3/Kv4.3 interaction

AuthorsCercós, Pilar ; Peraza, Diego A.; González, Teresa ; Mellström, Britt; Herranz, Rosario ; Martín-Martínez, Mercedes ; Naranjo, José Ramón; Valenzuela, Carmen ; Gutiérrez-Rodríguez, Marta
Issue Date2016
CitationRed de Excelencia SICI Consolider International Workshop (2016)
AbstractKChIP-3 (potassium channel interacting protein-3), also known as DREAM (Downstream Regulatory Element Antagonist Modulator) or calsenilin, is a multifunctional calcium binding protein that controls the expression level and/or the activity of several proteins related to calcium homeostasis, neuronal excitability and neuronal survival. The interest in KChIP-3 is based on its key role in the regulation of intracellular calcium levels. As a calcium-dependent transcriptional repressor, KChIP-3 is a master regulator of activity-dependent gene expression and controls genes important for calcium homeostasis such as the sodium/calcium exchanger-3 (NCX3), and Ltype calcium channels. As an auxiliary protein in the plasma membrane, KChIP-3 interacts with, and regulates, the gating of Kv4 potassium channels, L- and T-type voltage-dependent calcium channels and NMDA receptors. Considering that altered neuronal calcium homeostasis is a common feature of many neurodegenerative pathologies, the KChIP-3 modulation could open new avenues for the treatment of different neurodegenerative diseases. However, up to now, only three KChIP-3 binding molecules have been identified. Hence, there is a clear need for the development of chemical tools to modulate and characterize DREAM activity and its interactions. In this communication we report the rational design and synthesis of novel KChIP-3 binding molecules and their effects on the modulation of the KChIP-3/Kv4.3 interaction. The applied strategy involved structure-based drug design, synthesis and surface plasmon resonance (SPR) studies. Moreover, we have identified the ligand binding site by directed-mutagenesis studies. Additionally, whole-cell-patch-clamp assays have allowed the identification of interesting and potent modulators of the DREAM/Kv4.3 interaction.
DescriptionResumen del póster presentado al International Workshop de la Red de Excelencia SICI Consolider, celebrado en Torrecaballeros, Segovia (España) del 20 al 22 de octubre de 2016.
Appears in Collections:(IIBM) Comunicaciones congresos
(CNB) Comunicaciones congresos
(IQM) Comunicaciones congresos
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